Fragile X syndrome (FXS) results from a trinucleotide repeat expansion (full mutation;>200 CGG repeats) in the in the 5'untranslated region of the fragile X mental retardation 1 gene (FMR1) located at Xq27.3, leading to a reduction or absence of the gene's protein product, the FMR1 protein (FMRP), ultimately causing cognitive and behavioral impairments that are characteristic of the syndrome. Individuals with the FMR1 premutation (55-200 CGG repeats) are at risk for transmission of the gene in its expanded full mutation form in subsequent generations. Until recently, these "carriers" were believed to be clinically unaffected. However, following a period of scientific debate and controversy over this topic, recent evidence has emerged demonstrating that a proportion of these individuals have significant social, emotional, and cognitive problems, even autism and mental retardation in the most affected patients (Cornish, et al., 2005;Franke, et al., 1998;Goodlin-Jones, Tassone, Gane, &Hagerman, 2004;R. J. Hagerman &Hagerman, 2002;Johnston, et al., 2001;Moore, Daly, Schmitz, et al., 2004;Moore, Daly, Tassone, et al., 2004;Tassone, Hagerman, Taylor, Mills, et al., 2000). These deficits have previously been attributed to a mild deficit of FMRP that can occur in premutation carriers, especially those with higher CGG repeat alleles. In addition, we have discovered that male and rare female carriers are at significant risk for a neurodegenerative disease in later adulthood primarily characterized by intention tremor and gait ataxia called Fragile X-Associated Tremor Ataxia Syndrome (FXTAS, R. J. Hagerman, et al., 2001;Jacquemont, et al., 2003). This disease is not seen in FXS and has a different molecular mechanism involving, we believe, a toxic gain of function effect of abnormal elevation of FMR1 mRNA. This proposal does not involve FXTAS patients but rather younger men and women with the premutation who demonstrate psychiatric disturbances and are at risk for later neurodegeneration (Hessl, et al., 2005). The limbic region, especially the hippocampus and amygdala, appear to be especially impacted by increased CGG repeat size and the abnormal elevation of FMR1 mRNA (Abitbol, et al., 1993;Greco, et al., 2002;Jdkdld, et al., 1997;Moore, Daly, Tassone, et al., 2004) and we therefore focus on this region in the present study. This research will elucidate gene-brain-behavior associations related to the premutation that may provide insight into other disorders involving memory, social-emotional dysfunction, and the broader autism phenotype. The potential relevance of this work is significant given that the premutation occurs in an estimated 1 in 251 to 813 males and 1 in 113 to 259 females (Dombrowski, et al., 2002;Rousseau, Rouillard, Morel, Khandjian, &Morgan, 1995;Toledano-Alhadef, et al., 2001). PUBLIC HEALTH RELEVANCE: This research examines whether fragile X premutation carriers have emotional, social, or memory problems due to alterations in the structure or function of the limbic system of the brain. The premutation of the FMR1 gene is relatively common, affecting approximately 1 in 150 to 1 in 800 individuals. This research will help to clarify links between genes, brain, and behavior within this condition that may have implications for understanding of these types of mechanisms in other more common neuropsychiatric conditions.